Levodopa Administration Research Articles

Severity of Dyskinesia and D3R Signaling Changes Induced by L-DOPA Treatment of Hemiparkinsonian Rats Are Features Inherent to the Treated Subjects.

Extensive damage to nigrostriatal dopaminergic neurons leads to Parkinson’s disease (PD). To date, the most effective treatment has been administration of levodopa (L-DOPA) to increase dopaminergic tone. This treatment leads to responses that vary widely among patients, from predominantly beneficial effects to the induction of disabling, abnormal movements (L-DOPA induced dyskinesia (LID)). Similarly, experimental studies have shown animals with widely different degrees of LID severity. In this study, unilateral injections of 6-hydroxydopamine (6-OHDA) in the medial forebrain bundle (MFB) produced more than 90% depletion of dopamine in both the striatum and the substantia nigra reticulata (SNr) of rats. Population analysis showed that dopamine depletion levels were clustered in a single population. In contrast, analysis of abnormal involuntary movements (AIMs) induced by L-DOPA treatment of 6-OHDA-lesioned animals yielded two populations: one with mild LID, and the other with severe LID, which are also related to different therapeutic responses. We examined whether the severity of LID correlated with changes in dopamine 3 receptor (D3R) signaling because of the following: (a) D3R expression and the induction of LID are strongly correlated; and (b) dopaminergic denervation induces a qualitative change in D3R signaling in the SNr. We found that the effects of D3R activation on cAMP accumulation and depolarization-induced [3H]-gamma-aminobutyric acid ([3H]-GABA) release were switched. L-DOPA treatment normalized the denervation-induced changes in animals with mild LID. The D3R activation caused depression of both dopamine 1 receptor (D1R)-induced increases in cAMP production and depolarization-induced [3H]-GABA release, which were reversed to their pre-denervation state. In animals with severe LID, none of the denervation-induced changes were reversed. The finding that in the absence of identifiable differences in 6-OHDA and L-DOPA treatment, two populations of animals with different D3R signaling and LIDs severity implies that mechanisms intrinsic to the treated subject determine the segregation.

Acute L-DOPA administration reverses changes in firing pattern and low frequency oscillatory activity in the entopeduncular nucleus from long term L-DOPA treated 6-OHDA-lesioned rats

The pathophysiology of Parkinson's disease (PD) and L-DOPA-induced dyskinesia (LID) is associated with aberrant neuronal activity and abnormal high levels of oscillatory activity and synchronization in several basal ganglia nuclei and the cortex. Previously, we have shown that the firing activity of neurons in the substantia nigra pars reticulata (SNr) is relevant in dyskinesia and may be driven by subthalamic nucleus (STN) hyperactivity. Conversely, low frequency oscillatory activity and synchronization in these structures seem to be more important in PD because they are not influenced by prolonged L-DOPA administration. The aim of the present study was to assess (through single-unit extracellular recording techniques under urethane anaesthesia) the neuronal activity of the entopeduncular nucleus (EPN) and its relationship with LID and STN hyperactivity, together with the oscillatory activity and synchronization between these nuclei and the cerebral cortex in 6-OHDA-lesioned rats that received long term L-DOPA treatment (or not). Twenty-four hours after the last L-DOPA injection the firing activity of EPN neurons in long term L-DOPA treated 6-OHDA-lesioned rats was more irregular and bursting compared to sham rats, being those alterations partially reversed by the acute challenge of L-DOPA. No correlation between EPN neurons firing activity and abnormal involuntary movements score was found. However, there was a significant correlation between the firing activity parameters of EPN and STN neurons recorded from long term L-DOPA treated 6-OHDA-lesioned rats. Low frequency oscillatory activity and synchronization both within the EPN and with the cerebral cortex were enhanced in 6-OHDA-lesioned animals. These changes were reversed by the acute L-DOPA challenge only in long term L-DOPA treated 6-OHDA-lesioned rats. Altogether, these results obtained from long term L-DOPA treated 6-OHDA-lesioned rats suggest (1) a likely relationship between STN and EPN firing patterns and spiking phases induced by changes after prolonged L-DOPA administration and (2) that the effect of L-DOPA on the firing pattern, low frequency oscillatory activity and synchronization in the EPN may have a relevant role in LID.

Boosting Drug Discovery for Parkinson's: Enhancement of the Delivery of a Monoamine Oxidase-B Inhibitor by Brain-Targeted PEGylated Polycaprolactone-Based Nanoparticles.

The current pharmacological treatments for Parkinson’s disease only offer symptomatic relief to the patients and are based on the administration of levodopa and catechol-O-methyltransferase or monoamine oxidase-B inhibitors (IMAO-B). Since the majority of drug candidates fail in pre- and clinical trials, due largely to bioavailability pitfalls, the use of polymeric nanoparticles (NPs) as drug delivery systems has been reported as an interesting tool to increase the stealth capacity of drugs or help drug candidates to surpass biological barriers, among other benefits. Thus, a novel potent, selective, and reversible IMAO-B (chromone C27, IC50 = 670 ± 130 pM) was encapsulated in poly(caprolactone) (PCL) NPs by a nanoprecipitation process. The resulting C27-loaded PEGylated PCL NPs (~213 nm) showed high stability and no cytotoxic effects in neuronal (SH-SY5Y), epithelial (Caco-2), and endothelial (hCMEC/D3) cells. An accumulation of PEGylated PCL NPs in the cytoplasm of SH-SY5Y and hCMEC/D3 cells was also observed, and their permeation across Caco-2 and hCMEC/D3 cell monolayers, used as in vitro models of the human intestine and blood-brain barrier, respectively, was demonstrated. PEGylated PCL NPs delivered C27 at concentrations higher than the MAO-B IC50 value, which provides evidence of their relevance to solving the drug discovery pitfalls.

Cardiovascular alterations in rats with Parkinsonism induced by 6-OHDA and treated with Domperidone

After Alzheimer, Parkinson disease (PD) is the most frequently occurring progressive, degenerative neurological disease. It affects both sympathetic and parasympathetic nervous systems in a variable fashion. Cardiovascular symptoms are present in almost all stages of PD and narrower heart rate variability is the earliest sign. Administration of Levodopa to PD patients has proven to provide some degree of neurological protection. This drug, however, causes side effects including nausea and vomiting, lessened by the administration of domperidone. Autopsies in PD patients led some researchers to suggest the involvement of the ventricular arrhythmia induced by domperidone. The aim of the present study was to determine the impact of the adjusted human maximal dose of domperidone, on cardiological features of Wistar rats. domperidone was administered to both 6-hydroxydopamine Parkinsonism models and regular Wistar rats. Quantitative analysis of ranges of heart beat variation showed significant abnormal distribution in both groups receiving domperidone as compared with respective sham counterparts. However, qualitative analysis of Poincaré plots showed that 6-hydroxydopamine Parkinsonism models receiving domperidone had the narrowest full range of heart beat and the worst distribution heart beat ranges as compared with all study groups corroborating with previous suggestion that domperidone administration to PD patients is likely to play a role in sudden unexpected death in this group of patients.

Early onset peak-dose L-dopa induced dyskinesia in 55-year-old Ethiopian Parkinson’s disease patient

A case study of a 55-year-old newly diagnosed Parkinson’s disease patient naïve to L-dopa, who develop disabling early onset L-dopa induced dyskinesia (LID), which occurs immediately following L-dopa administration is presented. It is recommend to start with low dose L-dopa and to escalate slowly to avoid L-dopa included dyskinesia in dopamine naïve Parkinson’s disease patients.Keywords: Parkinson’s disease, L-dopa, peak-dose induced dyskinesia, 55-year-old male, Ethiopian

L-Dopa Modulation of Brain Connectivity in Parkinson's Disease Patients: A Pilot EEG-fMRI Study.

Studies of functional neurosurgery and electroencephalography in Parkinson’s disease have demonstrated abnormally synchronous activity between basal ganglia and motor cortex. Functional neuroimaging studies investigated brain dysfunction during motor task or resting state and primarily have shown altered patterns of activation and connectivity for motor areas. L-dopa administration relatively normalized these functional alterations. The aim of this pilot study was to examine the effects of L-dopa administration on functional connectivity in early-stage PD, as revealed by simultaneous recording of functional magnetic resonance imaging (fMRI) and electroencephalographic (EEG) data. Six patients with diagnosis of probable PD underwent EEG-fMRI acquisitions (1.5 T MR scanner and 64-channel cap) before and immediately after the intake of L-dopa. Regions of interest in the primary motor and sensorimotor regions were used for resting state fMRI analysis. From the EEG data, weighted partial directed coherence was computed in the inverse space after the removal of gradient and cardioballistic artifacts. fMRI results showed that the intake of L-dopa increased functional connectivity within the sensorimotor network, and between motor areas and both attention and default mode networks. EEG connectivity among regions of the motor network did not change significantly, while regions of the default mode network showed a strong tendency to increase their outflow toward the rest of the brain. This pilot study provided a first insight into the potentiality of simultaneous EEG-fMRI acquisitions in PD patients, showing for both techniques the analogous direction of increased connectivity after L-dopa intake, mainly involving motor, dorsal attention and default mode networks.

Levodopa/Benserazide PLGA Microsphere Prevents L-Dopa–Induced Dyskinesia via Lower β-Arrestin2 in 6-Hydroxydopamine Parkinson’s Rats

Prolonged pulsatile administration of Levodopa (L-dopa) can generate L-dopa–induced dyskinesia (LID). Numerous research has reported that continuous dopamine delivery (CDD) was useful in reducing the severity of LID. 6-OHDA lesioned rats were divided into two groups to receive intermittent L-dopa stimulation (L-dopa/benserazide) or Levodopa/benserazide PLGA microsphere (LBPM) for 3 weeks. rAAV (recombinant adeno-associated virus) vector was used to overexpress and ablation of β-arrestin2. We found that LBPM developed less AIM severity compared with standard L-dopa administration, whereas selective deletion of β-arrestin2 in striatum neurons dramatically enhanced the severity of dyskinesia by LBPM. On the contrary, the effects of LBPM in terms of ALO AIM were further relieved by β-arrestin2 overexpression. Furthermore, no significant change in motor behavior was seen either in inhibition or overexpression of β-arrestin2. In short, our experiments provided evidence that LBPM’s prevention of LID behavior was likely due to β-arrestin2, suggesting that a therapy modulating β-arrestin2 may offer a more efficient anti-dyskinetic method with a low risk of untoward effects.

Pharmacological Treatment Pattern and Comorbidities in Parkinson’s Disease Outpatients at Dr. Hasan Sadikin General Hospital Bandung in 2013–2018

Background : Parkinson’s disease (PD) is one of many neurodegenerative diseases with symptomatic management, and with the correct pattern of pharmacological treatment PD may have an improved quality of life for a minimum of three years. This study aimed to illustrate treatment patterns and comorbidities in PD patients at Dr. Hasan Sadikin General Hospital, Bandung. Methods : This study was a cross-sectional descriptive study by using total medical records of the period of 2013 to 2018. PD patients receiving pharmacological treatments such as levodopa, anticholinergics, dopamine agonists, or combined therapy were included. Patients with incomplete data and with the previous history of other neurological diseases before PD were excluded from this study. Results : In total, there were 57 patients with PD, of whom most of them were males (79%). Age-wise, PD was most common in 60 to 69-year-olds (32%). The most commonly used treatment pattern was the administration of levodopa (33%). Patients aged younger than 30 years were administered anticholinergics, whereas the older patients (>60 years old) mostly were given levodopa. Comorbidities after PD diagnosis were mostly stroke, dementia, and epilepsy. Conclusions : Males are most affected by PD, and the most commonly used treatment pattern is levodopa monotherapy. PD is most commonly found in patients aged 60 to 69 years. Patients aged below 30 years are administered anticholinergics. The most common comorbidities found are a stroke, followed by dementia and epilepsy. By recognizing the patterns and comorbidities of this disease, the study may provide some insights into choosing the most effective pharmacological therapy for PD.

Co-Administration of Aspirin and L-DOPA Against 6-OHDA-Induced Dopamine Neurotoxicity

Background: At present, L-DOPA remained the gold standard therapy for motor symptoms of Parkinson's disease (PD) patients. However, prolonged administration of L-DOPA led to the development of dyskinesia. Aspirin, a non-steroidal anti-inflammatory drug (NSAID), has been widely used to relieve pain and inflammation. Recent studies indicated that aspirin produced neuroprotection against DA neuronal loss in PD animal model. Methods: Rats lesioned with 6-hydroxydopamine (6-OHDA) in substantia nigra were employed and treated with L-DOPA and aspirin for 21 days. The movement disorders elicited by L-DOPA were determined by the abnormal involuntary movements (AIM) scores analysis. Finding: In 6-OHDA lesioned rat PD model, aspirin or L-DOPA evoked DA neuroprotection 7 days after treatment. Co-administration of aspirin and L-DOPA still conferred neuroprotection. In addition, aspirin attenuated the development of LID, as evidenced by the decreased AIM scores without interfering with L-DOPA efficacy 21 days after treatment. Furthermore, aspirin combined with L-DOPA inhibited microglia and astroglia activation and the subsequent neuroinflammatory responses. Importantly, aspirin didn't produce side effects during this neuroprotection. Interpretation: These results suggest that aspirin might have beneficial potential to attenuate L-DOPA efficacy and alleviate LID in PD. Funding Statement: National Natural Science Foundation of China (No. 81760658), foundation for High-level Innovative Talents of Guizhou Province (No. 20164027), Shijingshan's Tutor Studio of Pharmacology (No. GZS-201607), Innovation Research Group project of Education Department of Guizhou Province (No. 2016038), foundation for Excellent Young Talents of Zunyi Medical University (No.201603). Declaration of Interests: The authors have declared no any conflict of interests. Ethics Approval Statement: All animal experiments were performed in accordance with Chinese Guidelines of Animal Care and Welfare, and the present study was approved by the Animal Care and Use Committee of Zunyi Medical University (Zunyi, China).

Optostimulation of striatonigral terminals in substantia nigra induces dyskinesia that increases after L-DOPA in a mouse model of Parkinson's disease.

L-DOPA-induced dyskinesia (LID) remains a major complication of L-DOPA therapy in Parkinson's disease. LID is believed to result from inhibition of substantia nigra reticulata (SNr) neurons by GABAergic striatal projection neurons that become supersensitive to dopamine receptor stimulation after severe nigrostriatal degeneration. Here, we asked if stimulation of direct medium spiny neuron (dMSN) GABAergic terminals at the SNr can produce a full dyskinetic state similar to that induced by L-DOPA. Adult C57BL6 mice were lesioned with 6-hydroxydopamine in the medial forebrain bundle. Channel rhodopsin was expressed in striatonigral terminals by ipsilateral striatal injection of adeno-associated viral particles under the CaMKII promoter. Optic fibres were implanted on the ipsilateral SNr. Optical stimulation was performed before and 24hr after three daily doses of L-DOPA at subthreshold and suprathreshold dyskinetic doses. We also examined the combined effect of light stimulation and an acute L-DOPA challenge. Optostimulation of striatonigral terminals inhibited SNr neurons and induced all dyskinesia subtypes (optostimulation-induced dyskinesia [OID]) in 6-hydroxydopamine animals, but not in sham-lesioned animals. Additionally, chronic L-DOPA administration sensitised dyskinetic responses to striatonigral terminal optostimulation, as OIDs were more severe 24hr after L-DOPA administration. Furthermore, L-DOPA combined with light stimulation did not result in higher dyskinesia scores than OID alone, suggesting that optostimulation has a masking effect on LID. This work suggests that striatonigral inhibition of basal ganglia output (SNr) is a decisive mechanism mediating LID and identifies the SNr as a target for managing LID.

NF-\u03baB/c-Rel deficiency causes Parkinson\u2019s disease-like prodromal symptoms and progressive pathology in mice

BackgroundParkinson’s disease (PD), the most common neurodegenerative movement disorder, is characterized by dopaminergic nigrostriatal neuron loss and brain accumulation of Lewy bodies, protein aggregates mainly composed of α-synuclein. We reported that mice deficient for NF-κB/c-Rel (c-rel-/-) develop a late-onset parkinsonism. At 18 months of age, c-rel-/- mice showed nigrostriatal degeneration and accumulation of α-synuclein aggregates associated with a motor impairment responsive to L-DOPA administration. Being c-Rel protein a transcriptional regulator for mitochondrial anti-oxidant and antiapoptotic factors, it has been inferred that its deficiency may affect the resilience of “energy demanding” nigral dopaminergic neurons to the aging process. PD patients manifest a prodromal syndrome that includes olfactory and gastrointestinal dysfunctions years before the frank degeneration of nigrostriatal neurons and appearance of motor symptoms. According to the Braak staging, the onset of non-motor and motor symptoms relates to progressive ascendant diffusion of α-synuclein pathology in the brain. The aim of this study was to identify whether c-rel-/- deficiency is associated with the onset of premotor signs of PD and spatio-temporal progression of cerebral α-synuclein deposition.MethodsIntestinal and olfactory functions, intestine and brain α-synuclein deposition as well as striatal alterations, were assessed in c-rel-/- and control mice from 2 to 18 months of age.ResultsFrom 2 months of age, c-rel-/- mice displayed intestinal constipation and increasing olfactory impairment. At 2 months, c-rel-/- mice exhibited a mild α-synuclein accumulation in the distal colon. Moreover, they developed an age-dependent deposition of fibrillary α-synuclein that, starting at 5 months from the olfactory bulbs, dorsal motor nucleus of vagus and locus coeruleus, reached the substantia nigra at 12 months. At this age, the α-synuclein pathology associated with a drop of dopamine transporter in the striatum that anticipated by 6 months the axonal degeneration. From 12 months onwards oxidative/nitrosative stress developed in the striatum in parallel with altered expression of mitochondrial homeostasis regulators in the substantia nigra.ConclusionsIn c-rel-/- mice, reproducing a parkinsonian progressive pathology with non-motor and motor symptoms, a Braak-like pattern of brain ascending α-synuclein deposition occurs. The peculiar phenotype of c-rel-/- mice envisages a potential contribution of c-Rel dysregulation to the pathogenesis of PD.

Statistical Analysis Between the Routes of Administration of L-Dopa and Digestive Dysfunctions in Parkinson Disease

The aim of this study was to evaluate possible correlation between routes of administration of levodopa in patients diagnosed with Parkinson�s disease and the presence of digestive symptoms. We included in this study 31 patients diagnosed with Parkinson�s disease:14 patients were on oral levodopa and 17 patients were on intrajejunal administration of levodopa/carbidopa. Each patient was assessed using Non-motor Symptoms Questionnaire for Parkinson�s Disease regarding the dysfunction of gastrointestinal tract. The results of our study indicated that there is a different distribution of the digestive dysfunction between the two groups of patients. The study indicate that the constipation was more frequent in those patients with oral medication.

Increased Neural Activity in Mesostriatal Regions after Prefrontal Transcranial Direct Current Stimulation and l-DOPA Administration

Dopamine dysfunction is associated with a wide range of neuropsychiatric disorders commonly treated pharmacologically or invasively. Recent studies provide evidence for a nonpharmacological and noninvasive alternative that allows similar manipulation of the dopaminergic system: transcranial direct current stimulation (tDCS). In rodents, tDCS has been shown to increase neural activity in subcortical parts of the dopaminergic system, and recent studies in humans provide evidence that tDCS over prefrontal regions induces striatal dopamine release and affects reward-related behavior. Based on these findings, we used fMRI in healthy human participants and measured the fractional amplitude of low-frequency fluctuations to assess spontaneous neural activity strength in regions of the mesostriatal dopamine system before and after tDCS over prefrontal regions (n = 40, 22 females). In a second study, we examined the effect of a single dose of the dopamine precursor levodopa (l-DOPA) on mesostriatal fractional amplitude of low-frequency fluctuation values in male humans (n = 22) and compared the results between both studies. We found that prefrontal tDCS and l-DOPA both enhance neural activity in core regions of the dopaminergic system and show similar subcortical activation patterns. We furthermore assessed the spatial similarity of whole-brain statistical parametric maps, indicating tDCS- and l-DOPA-induced activation, and >100 neuronal receptor gene expression maps based on transcriptional data from the Allen Institute for Brain Science. In line with a specific activation of the dopaminergic system, we found that both interventions predominantly activated regions with high expression levels of the dopamine receptors D2 and D3.SIGNIFICANCE STATEMENT Studies in animals and humans provide evidence that transcranial direct current stimulation (tDCS) allows a manipulation of the dopaminergic system. Based on these findings, we used fMRI to assess changes in spontaneous neural activity strength in the human dopaminergic system after prefrontal tDCS compared with the administration of the dopamine precursor and standard anti-Parkinson drug levodopa (l-DOPA). We found that prefrontal tDCS and l-DOPA both enhance neural activity in core regions of the dopaminergic system and show similar subcortical activation patterns. Using whole-brain transcriptional data of >100 neuronal receptor genes, we found that both interventions specifically activated regions with high expression levels of the dopamine receptors D2 and D3.

Comparison of the Antiparkinson Activity of Levodopa, Memantine, and Guanidine-Containing Analogs of Amantadine and Memantine (IEM-2151 and IEM-2163) in Rats with Rotenone-Induced Parkinsonism

Rotenone-induced parkinsonism in rats is a widely used animal model of parkinsonism for studies of the antiparkinsonism activity of new substances. The guanidine derivatives of adamantane 1-adamantylguanidine hydrochloride (IEM-2151) and 3,5-dimethyl-1-adamantylguanidine hydrochloride (IEM-2163) given p.o. at a dose of 10 mg/kg had signifi cantly greater antiparkinsonism effects than levodopa at a dose of 20 mg/kg and memantine at a dose of 5 mg/kg, as they reduced the proportion of rats with severe oligokinesia 1.5–3 times more effectively than memantine and levodopa and, in contrast to memantine and levodopa, completely eliminated severe catalepsy in rats with rotenone-induced parkinsonism. IEM-2151 was the safest substance, as it prevented lethality among rats throughout the experiment, while memantine and levodopa increased lethality among the animals towards the end of the experiment. Combined p.o. administration of levodopa with IEM-2151 at the low doses of 10 and 5 mg/kg, respectively, produced a maximal synergistic antiparkinsonism effect, which was greater than the effects of each drug alone at twice the dose. The combination of IEM-2151 with levodopa at low therapeutic doses is a potentially effective and safe approach to the treatment of levodopa-refractory parkinsonism.

Inhibition of MPTP-induced α-synuclein oligomerization by fatty acid-binding protein 3 ligand in MPTP-treated mice

Accumulation and aggregation of α-synuclein (αSyn) triggers dopaminergic (DAergic) neuronal loss in Parkinson's disease (PD). This pathological event is partly facilitated by the presence of long-chain polyunsaturated fatty acids (LC-PUFAs), including arachidonic acid. The intracellular transport and metabolism of LC-PUFAs are mediated by fatty acid-binding proteins (FABPs). We previously reported that heart-type FABP (FABP3) interacts with αSyn, thereby promoting αSyn oligomerization in DAergic neurons in the substantia nigra pars compacta (SNpc) following 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. This αSyn oligomerization is prevented in Fabp3 gene knock out mice. We document a novel FABP3 ligand, MF1 (4-(2-(1-(2-chlorophenyl)-5-phenyl-1H-pyrazol-3-yl)phenoxy)butanoic acid), that inhibits αSyn accumulation in DA neurons, thereby inhibiting the oligomerization of αSyn, loss of DAergic neurons, and PD-like motor deficits in MPTP-treated mice. Chronic oral administration of MF1 (0.3 or 1.0 mg/kg/day) significantly improved motor impairments and inhibited MPTP-induced accumulation and oligomerization of αSyn in the SNpc, and in turn prevented loss of tyrosine hydroxylase (TH)-positive cells in the SNpc. MF1 administration (0.1, 0.3, or 1.0 mg/kg/day) also restored MPTP-induced cognitive impairments. Although chronic administration of l-DOPA (3,4-dihydroxl-l-phenylalanine; 25 mg/kg/day, i.p.) also improved motor deficits, it failed to improve the cognitive impairments. In addition, l-DOPA failed to inhibit DAergic neuronal loss and αSyn pathologies in the SNpc. In summary, the novel FABP3 ligand MF1 rescues MPTP-induced behavioural and neuropathological features, suggesting that MF1 may be a disease-modifying drug candidate for synucleinopathies.

Levodopa-induced dyskinesia is closely linked to progression of frontal dysfunction in PD

To assess the relationship between the development of levodopa-induced dyskinesia (LID) and longitudinal changes in cognition. In this retrospective cohort study, we recruited 119 patients with Parkinson disease (PD) who underwent baseline and follow-up neuropsychological evaluations and were treated with levodopa for >5 years. On the basis of LID development, the patients were classified as patients with LID (PD-LID+, n = 38) or without LID (PD-LID-, n = 81) within 5 years of levodopa administration. After adjusting for age, sex, years of education, body mass index, motor severity at baseline, and levodopa increment per year, we compared the rates of cognitive decline using linear mixed model and dementia conversion using survival analysis between the groups. Neuropsychological performances and the percentage of patients with mild cognitive impairment (MCI) at baseline did not differ between the groups. The PD-LID+ group showed faster declines in frontal executive function (p = 0.002) and global cognitive function. The conversion rate to dementia was significantly higher in the PD-LID+ group than in the PD-LID- group (adjusted hazard ratio [HR] 3.94, 95% confidence interval [CI] 1.76-8.82). Patients with MCI in the PD-LID+ group had a higher risk of PD dementia conversion than those with normal cognition (adjusted HR 6.08, 95% CI 1.25-29.56) or MCI (adjusted HR 4.05, 95% CI 1.14-14.43) in the PD-LID- group. These results demonstrated that LID was closely associated with the progression of cognitive decline, especially frontal executive dysfunction, and the development of PD dementia.

Chronic administration of the histamine H3 receptor agonist immepip decreases l-Dopa-induced dyskinesias in 6-hydroxydopamine-lesioned rats

Histamine H3 receptors (H3Rs) are co-expressed with dopamine D1 receptors (D1Rs) by striato-nigral medium spiny GABAergic neurons, where they functionally antagonize D1R-mediated responses. We examined whether the chronic administration of the H3R agonist immepip modifies dyskinesias induced by L-3,4-dihydroxyphenylalanine, L-Dopa (LIDs), in rats lesioned with 6-hydroxydopamine in the substantia nigra pars compacta, and the effect of D1R and H3R co-activation on glutamate and GABA content in dialysates from the dorsal striatum of naïve rats. The systemic administration (i.p.) of L-Dopa for 14days significantly increased axial, limb, and orolingual abnormal involuntary movements (AIMs) compared with the vehicle group. The chronic administration of the H3R agonist immepip alongside L-Dopa significantly decreased axial, limb, and orolingual AIMs compared with L-Dopa alone, but AIMs returned to previous values on immepip withdrawal. Chronic immepip was ineffective when administered prior to L-Dopa. The chronic administration of immepip significantly decreased GABA and glutamate content in striatal dialysates, whereas the administration of L-Dopa alone increased GABA and glutamate content. These results indicate that chronic H3R activation reduces LIDs, and the effects on striatal GABA and glutamate release provide evidence for a functional interaction between D1Rs and H3Rs.

Combining Gene Transfer and Nonhuman Primates to Better Understand and Treat Parkinson's Disease.

Parkinson’s disease (PD) is a progressive CNS disorder that is primarily associated with impaired movement. PD develops over decades and is linked to the gradual loss of dopamine delivery to the striatum, via the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). While the administration of L-dopa and deep brain stimulation are potent therapies, their costs, side effects and gradual loss of efficacy underlines the need to develop other approaches. Unfortunately, the lack of pertinent animal models that reproduce DA neuron loss and behavior deficits—in a timeline that mimics PD progression—has hindered the identification of alternative therapies. A complementary approach to transgenic animals is the use of nonhuman primates (NHPs) combined with the overexpression of disease-related genes using viral vectors. This approach may induce phenotypes that are not influenced by developmental compensation mechanisms, and that take into account the personality of animals. In this review article, we discuss the combination of gene transfer and NHPs to develop “genetic” models of PD that are suitable for testing therapeutic approaches.

Mesenchymal Stem Cells-derived Exosomes: A New Possible Therapeutic Strategy for Parkinson's Disease?

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder worldwide. Clinically, it is characterized by severe motor complications caused by a progressive degeneration of dopaminergic neurons (DAn) and dopamine loss. Current treatment is focused on mitigating the symptoms through administration of levodopa, rather than on preventing DAn damage. Therefore, the use and development of neuroprotective/disease-modifying strategies is an absolute need, which can lead to promising gains on PD translational research. Mesenchymal stem cells (MSCs)–derived exosomes have been proposed as a promising therapeutic tool, since it has been demonstrated that they can act as biological nanoparticles with beneficial effects in different pathological conditions, including PD. Thus, considering their potential protective action in lesioned sites, MSCs-derived exosomes might also be active modulators of the neuroregeneration processes, opening a door for their future use as therapeutical strategies in human clinical trials. Therefore, in this review, we analyze the current understanding of MSCs-derived exosomes as a new possible therapeutic strategy for PD, by providing an overview about the potential role of miRNAs in the cellular and molecular basis of PD.

The Effect of L-dopa on Postural Stability in Parkinson’s Disease Patients

The aim of the study was to evaluate the effects of L-dopa on postural stability in Parkinson’s disease patients. In the study, we examined a group of 13 patients, members of the Parkinson’s Association. The majority of subjects were women: 8 (61.538%), while 5 (38.462%) were men. These were patients with advanced, idiopathic Parkinson’s disease. The study was performed at the Posturology Laboratory of the Faculty of Medicine and Health Sciences, UJK, Kielce (Poland). The duration of the illness was longer than 5 years. The daily L-dopa dose was between 600 and 1000 mg/d. Patients were tested for postural stability prior to taking the morning dose and again, 1 h after the 200-mg dose (Madopar 250 Tablets). The Biodex Balance System was applied in order to perform Postural Stability Testing. No statistically significant differences were found for the distribution of postural stability results before or after L-dopa administration. Nonetheless, it should be noted that all variables in the Postural Stability Test were slightly improved following L-dopa administration. The highest percentage (% Time in Zone) was noted in Zone A (the best), before (85.77%) and after L-dopa administration (95.23%). The highest % Time in Quadrant was in Quadrant IV (right posterior) both before (41.43%) and after L-dopa administration (49.54%). When comparing the distribution of postural stability variables before and after L-dopa administration, there were no significant differences between women and men.